The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions wih dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of dragmacidin D and a several members of C30-sesquiterpenoid Nuphar thioalkaloids that display an array of biological activity associated with the inhibition of NFkB-regulated pathways. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and unknown human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.

Public Health Relevance

Complex molecules derived from nature continue to be important lead compounds for drug development in many therapeutic areas, especially in cancer, infectious diseases, and neurological disorders. Our goals are the development of methods and strategies to enable rapid and economical access to such compounds. Another specific goal is to use a novel class of marine toxins as probes to study the biology associated with nicotinic acetylcholine receptors and their effect on cholinergic signal transmission, which i implicated in a number of physiologically important processes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
Zip Code
Yu, Kai; Lu, Ping; Jackson, Jeffrey J et al. (2017) Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries. J Am Chem Soc 139:527-533
Martinez, Juliana A; Xiao, Qing; Zakarian, Armen et al. (2017) Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. Biochemistry 56:3150-3157
Molgó, Jordi; Marchot, Pascale; Aráoz, Rómulo et al. (2017) Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors. J Neurochem 142 Suppl 2:41-51
Ma, Yun; Mack, Kyle A; Liang, Jun et al. (2016) Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies. Angew Chem Int Ed Engl 55:10093-7
Alvarado, Joseph; Fournier, Jeremy; Zakarian, Armen (2016) Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C-O Bond Formation under Mild Conditions. Angew Chem Int Ed Engl 55:11625-11628
Mailyan, Artur K; Young, Kyle; Chen, Joanna L et al. (2016) Stereoselective Synthesis of Cyclic Guanidines by Directed Diamination of Unactivated Alkenes. Org Lett 18:5532-5535
Lu, Ping; Herrmann, Aaron T; Zakarian, Armen (2015) Toward the Synthesis of Nuphar Sesquiterpene Thioalkaloids: Stereodivergent Rhodium-Catalyzed Synthesis of the Thiolane Subunit. J Org Chem 80:7581-9
Jackson, Jeffrey J; Kobayashi, Hiroyuki; Steffens, Sophia D et al. (2015) 10-Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)-Dragmacidin?D. Angew Chem Int Ed Engl 54:9971-5
Bourne, Yves; Sulzenbacher, Gerlind; Radi?, Zoran et al. (2015) Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal ?7 from Muscle ?1(2)??? nAChRs. Structure 23:1106-15
Stivala, Craig E; Benoit, Evelyne; Aráoz, Rómulo et al. (2015) Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins. Nat Prod Rep 32:411-35

Showing the most recent 10 out of 34 publications